Diagnostic challenges in breast pathology

Pathology (2013) 45(S1), pp. S7–S11

Anatomical Pathology, Oral and Maxillofacial Pathology including workshops

METABOLIC LIVER DISEASES: THE CHANGING APPROACH TO DIAGNOSIS – THE ROLE OF ANATOMICAL PATHOLOGY C. W. Chow The Royal Children’s Hospital, Melbourne, Vic, Australia The diagnosis of metabolic diseases affecting the liver in children is a team approach involving the paediatrican, geneticist, metabolic physician, biochemist, molecular biologist and the anatomical pathologist. With the advancement in biochemistry and molecular genetics in the last four decades, the role of anatomical pathology has become very small. It is now exceptionally rare for it to be used in the diagnosis of lysosomal, peroxisomal and fatty acid metabolic disorders. It is still used in some glycogenosis and diseases of mitochondrial dysfunction. For this, electron microscopy is essential, and when a liver biopsy is performed without a clear diagnosis, it is highly desirable to process a tiny part for ultrastructure, which can then be performed if considered useful after correlation of the light microscopy with clinical features. Lysosomes, peroxisomes, mitochondria, glycogen particles and lipid should be systematically checked as a routine. At autopsy tissues should be urgently retrieved for metabolic studies. However this should not replace a full autopsy when the presence and nature of a metabolic disease is uncertain. As this is a very specialised area and the number of cases is very small, expertise should be concentrated. The role of anatomical pathology must be regularly reviewed and updated.

METABOLIC LIVER DISEASES: THE CHANGING APPROACH TO DIAGNOSIS – THE ROLE OF BIOCHEMICAL AND MOLECULAR GENETIC TESTING K. H. Carpenter NSW Biochemical Genetics Service, The Children’s Hospital at Westmead, Westmead, NSW, Australia The investigation of a child with hepatic disease must include the large number of inherited metabolic conditions with a primary liver presentation. First line clues come from routine biochemistry with information from liver function tests supported by evidence of hypoglycaemia and/or renal tubular dysfunction. More specific biochemical genetic testing usually commences with urine organic and amino acids. These may reveal pathognomonic metabolites leading directly to a firm diagnosis and treatment regimen, e.g., tyrosinaemia type I or citrin deficiency. More often they give clues to the metabolic pathway involved but further specialised testing is required to confirm the diagnosis, e.g., fatty acid oxidation defects. Clinical clues pointing to peroxisomal disorders can be pursued by analysis of very long chain fatty acids in plasma and enzymology for lysosomal storage disorders can be performed on leucoytes. The mitochondrial respiratory chain defects are difficult

to identify on metabolite assays. A portion of tissue taken at liver biopsy should be snap frozen on dry ice and stored at −80°C for respiratory chain enzymology if required. Biochemical diagnosis has traditionally been confirmed by mutation detection using traditional PCR and Sanger sequencing of the target gene or genes. It is now becoming feasible and cost effective to perform targeted exome capture or whole exome or genome sequencing to identify the genetic defect in patients with metabolic liver disease.

AN APPROACH TO NON-NEOPLASTIC RENAL BIOPSIES Jeffrey Searle Sullivan Nicolaides Pathology, Brisbane, Qld, Australia The justification for a renal biopsy is its ability to provide information on diagnostic and prognostic features, and to guide management. These properties are considerably enhanced by close liaison between the reporting pathologist and the attending renal physician. The tissue is obtained almost invariably by percutaneous needle biopsy under ultrasound or CT guidance, and the proper handling of the sample to ensure an accurate diagnosis or a reasonable explanation to correlate with the clinical findings is essential. This handling will be outlined during the presentation, along with recommendations for processing the biopsy and its sectioning. The series of stains used at various levels that are regularly scrutinised for diagnostic assessment will be described. The kidney reacts in a limited number of ways to various types of injuries (e.g., infectious, immunological, toxic, haemodynamic, obstructive and metabolic) to produce a limited range of morphological lesions. Similarly, there are a limited number of clinical syndromes that manifest renal disease to match these morphological findings. Examples of the range of morphological appearances commonly encountered in renal biopsy interpretation will be presented and described, and this range (along with specific disease processes that produce them) will be made available online (courtesy of the RCPA).

DIAGNOSTIC CHALLENGES IN BREAST PATHOLOGY Sunil R. Lakhani Pathology Queensland, The University of Queensland School of Medicine, and the UQ Centre for Clinical Research, The Royal Brisbane & Women’s Hospital, Herston, Qld, Australia The use of needle core biopsies to evaluate abnormalities identified on breast screening is now well established. This together with an incomplete knowledge of the natural history of many disease processes has led to diagnostic challenges in the accurate classification of breast disease.

Print ISSN 0031-3025/Online ISSN 1465-3931 © 2013 Royal College of Pathologists of Australasia

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S8

Pathology (2013), 45(S1)

PATHOLOGY 2013 ABSTRACT SUPPLEMENT

Many of the diagnostic problems reside in the B3 category, which comprises a heterogeneous group of proliferations that include atypical ductal hyperplasia (ADH), lobular neoplasia (ALH/LCIS), columnar cell lesions (CCL) and flat epithelial atypia (FEA), radial scar (RS/CSL), phyllodes tumours, papillary lesions, mucinous lesions and spindle cell proliferations. In clinical practice, the rate of B3-biopsies ranges from 3% to 10%. In this lecture, I will cover some of the diagnostic issues and the changing classification related to papillary lesions of the breast and columnar cell lesions with and without atypia. These lesions form a significant component of consult practice throughout the world, suggesting that the diagnostic criteria and classification systems are far from robust. Suggested reading Lakhani SR, Ellis IO, Schnitt SJ, et al., editors. WHO Classification of Tumours of the Breast. Lyon: IARC, 2012.

LUNG CARCINOMA – ‘NONSMALL CELL’ IS NO LONGER AN OPTION Douglas W. Henderson, Sonja Klebe Department of Surgical Pathology, SA Pathology, Flinders Medical Centre, Bedford Park, SA, Australia Current diagnostic issues concerning nonsmall cell lung carcinoma (NSCLC) include subtyping as encountered in cytology and small biopsy samples, and the requirement to strike a balance between histology and immunohistochemistry (IHC) for discrimination between squamous (SCCs) and adenocarcinomas (ADCs), versus the requirement for conservation of material for molecular studies (i.e., for recognition of ADCs with EGFR, EML4-ALK, or other mutations). There is a problem for pathologists in subtyping of NSCLC from small biopsies, in relation to: (i) a minimal sample of poorly differentiated tumour for histological and IHC assessment; (ii) biopsy artefact; (iii) conservation of tissue for molecular studies. A minimalist IHC workup of p63 and TTF1 can facilitate discrimination between SCC versus nonmucinous ADC, respectively. However, about one-third of proven ADCs show expression of p63, so that a p63+/TTF1+ immunoprofile is still considered to favour ADC. Alternatively, p40 can be substituted for p63 and labels ADCs less often than p63, or CK5 or CK5/6 can be added to p63 to facilitate diagnosis of SCC. Invasive mucinous ADC has an immunoprofile different from nonmucinous ADC (usually CK7+/CK20+/TTF1–). Other pitfalls exist: TTF1+/p63– in small cell carcinoma and metastatic thyroid carcinoma; TTF1–/p63– in lymphomas and melanoma; and TTF1–/p63+ in metastatic urothelial carcinoma. In this context, IHC studies need to take into account the clinical background and medical history for each case. Even now, up to about 30% NSCLCs are not further classifiable beyond NSCLC NOS, on the basis of IHC on small biopsy samples. EGFR antibodies are commercially available, and can be used to screen for such mutations, whereas ALK antibodies used at present for diagnosis of ALK positive large cell lymphomas are insensitive for diagnosis of most EML4-ALK ADCs. ALK positive ADCs reported to date have been positive for TTF1, and positive/negative TTF1 labelling may represent an inclusionary/exclusionary boundary for molecular testing. Even so, EGFR and ALK ADCs represent a small proportion of ADCs in Western societies, so that histological/IHC subtyping appears to retain prognostic and clinical relevance for most ADCs.

MUTATION TESTING IN CANCER – OPPORTUNITIES AND CHALLENGES FOR PATHOLOGISTS Sandra A. O’Toole1,2,3 1Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, 2Sydney Medical School, University of Sydney, Camperdown, and 3The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia An essential part of personalised medicine is the development of suitable companion diagnostics to stratify patients by specific molecular lesions that are sensitive to targeted therapies. In recent years there have been impressive responses in a subset of patients with specific somatic changes in genes encoding tyrosine kinase receptors such as HER2 in breast cancer, ALK and EGFR in lung cancer and BRAF in melanoma. However, there are significant challenges in implementing high quality, timely and cost effective molecular testing in a routine diagnostic setting, often on very small tissue samples containing a mixture of normal and malignant cells with damaged DNA. Furthermore, the volume of data from new high throughput technologies and the subsequent identification of multiple new targets, which may occur at very low frequencies, imposes additional pressures. Our own experience at Royal Prince Alfred Hospital has highlighted that a multidisciplinary approach between radiologists, physicians, surgeons, tissue and genetic pathologists is essential to ensure optimal diagnosis and therapy of patients. We have also found that use of sensitive, well validated, mutation specific antibodies provides additional confidence in the results of genetic assays and may help select patients for expensive and labour intensive molecular testing. Multigene mutation assays offer significant advantages for the personalisation of many malignancies. A PRACTICAL APPROACH TO THE DIAGNOSIS OF BRAIN TUMOURS Michael Buckland1, Barbara Koszyca2 of Neuropathology, Royal Prince Alfred Hospital and The University of Sydney, Sydney, 2Hanson Institute Centre for Neurological Diseases, SA Pathology, Adelaide, and Discipline of Anatomy and Pathology, University of Adelaide, Adelaide, SA, Australia 1Department

The diagnosis of intra-axial brain tumours presents a number of challenges which are undoubtedly made more daunting by the unique nature of the organ affected. Rather than highlighting recently described entities, which are both rare and well described in the literature, the masterclass will aim to provide an approach for pathologists that encompasses intraoperative preparations, formal histopathology and the molecular aspects of diagnosis. Diagnostic problems that will be covered from a histologist’s point of view include the difficulties and pitfalls that may be encountered in grading glial tumours, common histological mimics and what is really required to make the diagnosis of a glioneuronal tumour. WHITHER CARCINOID? NEUROENDOCRINE TUMOURS IN 2013 Chris Hemmings ACT Pathology, Canberra, and Australian National University, Canberra, ACT, Australia Neuroendocrine tumours are a diverse group of neoplasms which may arise in many organs and which display variable clinical

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